中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (12): 2708-2722.doi: 10.4103/NRR.NRR-D-23-01498

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

巨噬细胞向 M1 表型极化过程中的动脉粥样硬化相关lnc_000048/PKR/STAT1轴

  

  • 出版日期:2024-12-15 发布日期:2024-03-30
  • 基金资助:
    国家自然科学基金；河南省高等学校重点科研项目

Repressing iron overload ameliorates central post-stroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

He Fang1, #, Mengjie Li1, #, Jingchen Yang2, #, Shunping Ma3, Li Zhang1, Hongqi Yang4, Qiongyan Tang1, Jing Cao5, 6, *, Weimin Yang1, *   

  1. 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 2Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; 3Department of Nutrition, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 4Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, Henan Province, China; 5Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China; 6Neuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, Henan Province, China
  • Online:2024-12-15 Published:2024-03-30
  • Contact: Jing Cao, PhD, caojing@zzu.edu.cn; Weimin Yang, MD, weiminyanghn@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. U2004106 (to WY), 81971061 (to JC); the Key Scientific Research Project of Colleges and Universities in Henan Province, No. 21A320039 (to WY).

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摘要：

脑卒中后中枢性疼痛是累及丘脑的脑血管意外的后遗症之一，但其诊断和治疗困难，患者遭受慢性躯体疼痛，分子机制仍不清楚。既往研究证实钾电压门控通道亚家族成员2 (Kv1.2)在脊柱中的表达与疼痛相关。因此，离子通道的变化可能也在脑卒中后中枢性疼痛中发挥重要作用。实验结果显示，HDAC2-Kv1.2信号轴在脑卒中后中枢性疼痛中发挥着关键作用，并且抑制脑出血后铁过载可逆转脑卒中后中枢性疼痛的发生。首先在脑卒中后中枢性疼痛大鼠血肿周围组织中观察到Kv1.2表达下降，并证实Kv1.2的下调诱导了疼痛过敏，接着通过体内外实验发现脑卒中后中枢性疼痛大鼠丘脑中HDAC2过度激活可通过调控Kcna2基因的表观遗传沉默增加神经元兴奋性，从而诱导痛觉过敏。此外，还发现铁螯合剂去铁酮的应用可以逆转脑卒中后中枢性疼痛大鼠 HDAC2 和 Kv1.2 表达变化，从而减轻脑卒中后中枢性疼痛大鼠模型中的痛觉过敏。上述结果提示，脑出血后铁过载可能导致HDAC2过度表达，从而抑制Kcna2的表达并在脑卒中后中枢性疼痛大鼠模型中诱导疼痛敏化。实验揭示了脑卒中后中枢性疼痛的潜在机制，为脑卒中后中枢性疼痛的预防和治疗提供了可能的治疗靶点。

https://orcid.org/0000-0003-3124-4780 (Jing Cao); https://orcid.org/0000-0003-2265-7532 (Weimin Yang)

Abstract: Thalamic hemorrhage can lead to the development of central post-stroke pain. Changes in histone acetylation levels, which are regulated by histone deacetylases, affect the excitability of neurons surrounding the hemorrhagic area. However, the regulatory mechanism of histone deacetylases in central post-stroke pain remains unclear. Here, we show that iron overload leads to an increase in histone deacetylase 2 expression in damaged ventral posterolateral nucleus neurons. Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium (Kv) channel subunit gene in a rat model of central post-stroke pain, thereby increasing Kcna2 expression and relieving central pain. However, in the absence of nerve injury, increasing histone deacetylase 2 expression decreased Kcna2 expression, decreased Kv current, increased the excitability of neurons in the ventral posterolateral nucleus area, and led to neuropathic pain symptoms. Moreover, treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage, reversed histone deacetylase 2 upregulation and Kv1.2 downregulation, and alleviated mechanical hypersensitivity in central post-stroke pain rats. These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation, mediated by iron overload, are important factors in central post-stroke pain pathogenesis and could serve as new targets for central post-stroke pain treatment.

Key words: central post-stroke pain, hemorrhagic stroke, histone deacetylase, iron overload, voltage-gated potassium ion channel 1.2